[The syndrome of inappropriate diuretic hormone secretion (SIADH) ending lethal during the use of paliperidon and lamotrigine]. / Het syndroom van inadequate secretie van het antidiuretisch hormoon (SIADH) met letale afloop tijdens gebruik van paliperidon en lamotrigine.

Hyponatremia, as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), is well known with the use of nearly all antipsychotics and mood stabilizers. The first symptoms are atypical and are not always mentioned by the patient. However, not recognising the syndrome in due time can be lethal. We describe a 35-year-old woman who died due to lack of recognition of SIADH. The patient, who had a bipolar disorder and was for a long time on a paliperidone depot, developed complaints of nausea, vomiting and thirst after lamotrigine was prescribed. A few days after increasing the dose, she died; no evidence was found of suicide. The SIADH was probably triggered by the use of lamotrigine and paliperidone. Paying sufficient attention to the symptoms that may cause this syndrome, as well as their early recognition, could save lives.

[Pimavanserin: a new treatment for the Parkinson's disease psychosis]. / Pimavanserine: een nieuwe behandeling voor psychose bij de ziekte van Parkinson.

BACKGROUND: Clozapine is an effective drug for treating psychosis in Parkinson's disease (PDP) and is registered as such in the Netherlands. However, clozapine can have adverse effects, including agranulocytosis. The new drug pimavanserin was recently registered in the United States for the treatment of PDP.
AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.
METHOD: Systematic search of the literature.
RESULTS: We found reports on four randomised controlled trials (RCTs), one review and six articles about the pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an effective treatment for PDP, and, like clozapine, it has very few negative effects on motor skills. However, all of the RCTs were funded by the manufacturer of pimavanserin and the trials were conducted in a very selective patient population. This means that results cannot be generalised. Long-term results are not yet available. In earlier trials clozapine was shown to have a greater and faster antipsychotic effect. Many clinicians and psychiatrists have a great deal of experience with this drug. Another important point is that no-one has yet conducted a trial comparing clozapine and pimavanserin.
CONCLUSION: Given that the current second drug of choice, namely quetiapine, has not been found to be effective for PDP, we are of the opinion that - if pimavanserin is registered in the Netherlands - pimavanserin could be used when the current drug of choice, clozapine, is not completely effective or is poorly tolerated. For patients who have cognitive impairments in addition to psychosis, we advise testing the patient's reaction to a cholinesterase inhibitor before starting the patient on a course of antipsychotics.

Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network.

Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.

Caged probes: a novel tool in studying symplasmic transport in plant tissues.

Caged probes offer a novel approach to study plant cell-to-cell communication. Instead of introducing fluorescent molecules into cells by microinjection, their caged counterparts can be preloaded into the tissue by diffusion. Following spatially controlled photoactivation, movement of the uncaged fluorochrome can be followed in time and direction by confocal laser scanning microscopy. In the onion bulb scale epidermis used as a model system, symplasmic transport of the tracer out of a target cell was followed. Transport via the symplasmic pathway was challenged by plasmolysing the tissue. The experiments confirmed the symplasmic nature of tracer transport.

Focal adhesion kinases: interest in immunoendocrinology, developmental biology, and cancer.

The research field on focal adhesion-related kinases started a decade ago, but the term focal adhesion was introduced for the first time nearly 20 yr before. Since its identification, many studies have enlightened the role of the first intermediate of focal adhesion-related signals in a large number of biologic and physiologic processes. In this review, we try to integrate the most recent data about the known focal adhesion-related kinases, and we focus on three topics in which they deserve great interest: neuroendocrine-immune interactions, developmental biology, and proliferative diseases.

Distribution and kinetics of 131I-labeled human IgM monoclonal antibody 16.88 in patients with advanced colorectal cancer.

Sequential immunoscintigrams were used to describe the relative distribution and kinetics of 8 mg 131I-labeled human IgM monoclonal antibody 16.88 in 20 patients with colorectal cancer. The results show that the initial activity was higher and the clearance rate was faster (P < 0.05) from the left ventricle and liver than from most organs. In bone marrow the reverse was observed (P < 0.05). The biological half-life of 131I(-16.88) in tumor tissue (range 35.4-47.5 h) was longer (P < 0.01) than that in normal tissue (30.2-41.9 h). The image contrast ratio between liver metastases and background increased from 0.8 to 1.3 and for lesions outside the liver from 1.1 to 1.6. The estimated effective dose equivalent was 0.12 mSv/MBq. A second infusion 2 weeks after the first with the addition of unlabeled 16.88 up to 1000 mg for improvement of tumor tissue uptake was not of clinical relevance.

Gallium-67 radiotoxicity in human U937 lymphoma cells.

Promising clinical results have been obtained with radiolabeled antibodies in lymphoma patients. The higher uptake by lymphomas of 67Gallium (67Ga) compared with monoclonal antibodies makes selective radiotherapy by the widely available 67Ga appealing. However, the gamma radiation of 67Ga used in scintigraphy is considered to be almost non-toxic to lymphoma cells. However, in addition to photon radiation 67Ga emits low energy Auger electrons and 80-90 keV conversion electrons which could be cytotoxic. The objective of the present study was the assessment of radiotoxicity of 67Ga on a lymphoid cell line: U937. Proliferation (MTT-assay) and clonogenic capacity (CFU-assay) were measured after 3 and 6 days incubation with 10, 20 and 40 microCi ml-1 67Ga. Growth inhibition was 36% after 3 days incubation and 63% after 6 days incubation with 40 microCi 67Ga ml-1. Clonogenic capacity was reduced by 51% after 3 days and 72% after 6 days incubation with 40 microCi ml-1 67Ga. A survival curve showed an initial shoulder and became steeper beyond 200-250 pCi cell-1 (low linear energy transfer type). Iso-effect doses of 67Ga and 90Yttrium (90Y) were determined. The iso-effect dose of 40 microCi 67Ga ml-1 (cumulative dose of conversion electrons 306 cGy) was 2.5 microCi 90Y ml-1 (cumulative dose 494 cGy) and the iso-effect dose of 80 microCi 67Ga ml-1 was 5.0 microCi 90Y/ml. The main cytotoxic effect of 67Ga seems to be induced by the 80 keV conversion electrons. We conclude that the conversion electrons of 67Ga have a cytotoxic effect on U937 cells and that in our experiments a 16-fold higher microCi-dose of 67Ga than of 90Y was needed for the same cytotoxic effect. We believe that 67Ga holds promise for therapeutic use.

Radioimmunoscintigraphy of head and neck cancer using 99mTc-labeled monoclonal antibody E48 F(ab')2.

The diagnostic value of 99mTc-labeled monoclonal antibody E48 F(ab')2 (750 MBq, 1 mg) was evaluated in 10 patients with a histologically proven squamous cell carcinoma of the head and neck and with clinical evidence of cervical lymph node involvement. Preoperative findings on lymph node status obtained by radioimmunoscintigraphy (RIS), computerized tomography, magnetic resonance imaging, and palpation were defined per side (left and/or right side of the neck) as well as per lymph node level (I through V) and compared with the histopathological outcome of the neck dissection specimen. In 10 patients, all 8 known tumors at the primary site were detected by RIS. Furthermore, RIS was correct in 13 of 13 tumor involved neck sides and in 17 of 20 tumor involved lymph node levels. False-negative observations comprised 3 levels containing tumor deposits smaller than 1 cm in diameter, 2 of which were not detected by any other diagnostic modality. Palpation, computerized tomography, and magnetic resonance imaging were correct in, respectively, 13, 15, and 15 of the 20 tumor involved levels. There were 2 false-positive observations with monoclonal antibody E48 and 3 with palpation. No false-positive detections occurred with computerized tomography or magnetic resonance imaging. In two of the patients, RIS provided clinically important information which was not provided by any other diagnostic method. In one patient, recurrence of laryngeal carcinoma was established at the primary site after previous radiotherapy. In another patient, bilateral instead of unilateral lymph node involvement became apparent. These preliminary data indicate that radioimmunoscintigraphy with monoclonal antibody E48 may be helpful in the diagnosis of metastatic and recurrent head and neck cancer.

Determination of 4-aminopyridine in serum by solid-phase extraction and high-performance liquid chromatography.

An assay for the determination of 4-aminopyridine in serum has been developed using 3,4-diaminopyridine as internal standard and reversed-phase high-performance liquid chromatography with detection at 244 nm. A mobile phase of acetonitrile-methanol-ethanol-1% ammonium carbonate (75:10:10:5) provided excellent separation of both compounds. Samples were extracted on solid-phase columns. The linearity, precision, recovery and the limit of detection were all sufficient for the routine use of this assay in clinical studies of patients treated with 4-aminopyridine.

Performance characteristics of a 511-keV collimator for imaging positron emitters with a standard gamma-camera.

Line-source experiments were conducted to assess the performance of a gamma-camera equipped with a specially designed 511-keV collimator for the planar imaging of positron emitters. The results were compared with the camera performance with routinely used collimators and radionuclides (thallium-201, technetium-99m and gallium-67). With positron emitters, scatter contributed less to the widening of the line spread function than with radionuclides emitting lower photon energies. These observations can be explained by the relative deterioration in the discrimination power of the gamma-camera to reject scattered radiation at low energies. Planar 511-keV imaging may provide relevant clinical information, as we showed by fluorodeoxyglucose studies in a patient with a myocardial infarction and in a patient with a malignant lymphoma. It is concluded that positron emitters can be effectively applied for planar imaging with the generally available gamma-cameras. This study implies that radiotracers developed for positron emission tomography may find a place in the practice of conventional nuclear medicine.

Human IgM monoclonal antibody 16.88: pharmacokinetics and immunogenicity in colorectal cancer patients.

Twenty colorectal cancer patients were given an intravenous injection of human IgM monoclonal antibody (MAb) 16.88 (8 mg) conjugated to 131I for tumor localization. After a 2-week interval, a second injection with 200, 500, or 1000 mg of unlabeled antibody added was given to groups of five patients each. at the end of the 2-hour infusion, 66% of the radioactivity remained in the circulation. Blood clearance of the 131I-labeled MAb 16.88 was biphasic with a mean half-life (T1/2 alpha) of 12 hours and T1/2 beta of 45 hours. Clearance rate was 0.09 L/hour. More than 90% of the 131I in serum was protein bound, with an immunoreactive fraction of 80% in the first 48 hours. Size exclusion chromatography indicated no degradation products other than 131I in serum and urine. The urinary excretion rate of 131I increased to 1.5% of the dose per hour at 24 hours, with 50% of the dose excreted in 34 hours. The pharmacokinetic profile of 131I-labeled MAb 16.88 was neither influenced by the total protein dose of antibody administered nor affected by specific uptake in tumor tissue in individual patients, as determined on early immunoscintigrams. The larger antibody doses showed a slightly slower excretion of 131I. The assays applied to determine immunogenicity were enzyme-linked immunosorbent assay, radioimmunoassay, and the dot-blot assay. They had sensitivities ranging from 5 ng/mL to 0.5 micrograms/mL for goat or rabbit antihuman IgM. The assays did not reveal antihuman antibody responses.

Antibiotic concentrations in the groin wound after vascular prosthetic implantation.

The kinetics of systemically and locally administered cefuroxime or ceftazidime in wound fluid were investigated in the period after vascular prosthetic implantation. Cefuroxime or ceftazidime was administered intravenously in patients. Simultaneously 250 mg ceftazidime or cefuroxime was added to preclotted blood. Locally administered antibiotics could not be detected in our samples. In groin fluid samples 24-48 h after the operation the average concentration of cefuroxime was 8.3 and of ceftazidime 5.0 mg/l. The decline of the concentration of cefuroxime or ceftazidime in groin fluid seems to be much slower than one would expect from the half-lives of the antibiotics. We conclude that cefuroxime and to a lesser extent ceftazidime are suitable as prophylactic agents in arterial reconstruction.

Tumour localisation with 131I-labelled human IgM monoclonal antibody 16.88 in advanced colorectal cancer patients.

Human IgM monoclonal antibody 16.88 recognised an intracellular antigen strongly expressed in colorectal cancer tissue in 51% of our patients. Tumour localisation was carried out with 185 MBq 131I-16.88 (8 mg) in 20 of these patients with advanced disease. In 16 patients (80%) immunoscintigraphy was positive in at least one organ site with disease. Of all sites, 55% could be visualized. In general, lesions less than 3 cm could not be detected. Sequential immunoscintigrams of liver metastases showed variable patterns. Initial "cold" lesions corresponded to liver metastases with poor blood supply as indicated by 99mTc-sulphur-colloid and 99mTc-HMPAO scintigraphy, respectively. The mean (S.D.) biological half-life (whole body clearance of radioactivity) was 37.6 (5.0) h. A second infusion of 131I-16.88 with the addition of high doses of unlabelled 16.88 could be done safely, but did not result in better visualisation of tumour lesions or affect radioactivity clearance from the body.

Human IgM monoclonal antibody 16.88: pharmacokinetics and distribution in mouse and man.

Human IgM monoclonal antibody (MAb) 16.88 recognizes an antigen strongly expressed by colon cancer tissue. We used 131I-labelled 16.88 for biodistribution and pharmacokinetic studies in nude mice bearing WiDr or NIH:OVCAR-3 xenografts. Serum half-life was 8 h. Maximum tumour uptake was between 1 and 8 h after administration and amounted to, respectively, 3% and 1% of the injected dose g-1 for WiDr and NIH:OVCAR-3 tumours. Half-lives in these tumours were approximately 24 h. Tumour to normal colon uptake ratios increased from 2.3 at 24 h to 17 at 5 days after injection. Simultaneously, pharmacokinetic studies were performed in patients with advanced colon cancer reactive with 16.88. They were injected with 5 mCi 131I-16.88 by intravenous infusion over 2 h. Serum half-life was 20 h with greater than 90% of the 131I bound to 16.88. Within 40 h 50% of the injected dose was excreted as free 131I in the urine. In one patient an accelerated clearance was found, possibly caused by pre-existing antibodies reacting with 16.88. None of the patients showed an immune response against 16.88 antibody. Immunoscintigraphy showed positive tumour localization in the majority of the patients, best visualized at later days. We conclude that 16.88 has tumour localization properties while its human origin accounts for the lack of immunogenicity.

Sorption of various drugs in polyvinyl chloride, glass, and polyethylene-lined infusion containers.

The sorption of chloroquine sulfate, diazepam, isosorbide dinitrate, lorazepam, midazolam, nitroglycerin, promethazine hydrochloride, thiopental sodium, and warfarin sodium to three types of containers was studied. Appropriate amounts of the drugs were added to 500 mL of 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags, glass bottles, and Clear-Flex bags composed of a laminate of polyethylene, nylon, and polypropylene. The containers were stored in the dark at room temperature for 24 hours. Samples were taken at various intervals and assayed for drug concentration by high-performance liquid chromatography. There were no appreciable changes in pH after 24 hours, and all the admixtures remained clear and colorless. The potency of chloroquine sulfate, lorazepam, midazolam, promethazine hydrochloride, and thiopental sodium remained unchanged in glass, PVC, and Clear-Flex containers. Diazepam, isosorbide dinitrate, nitroglycerin, and warfarin sodium did not show any sorption to glass bottles and Clear-Flex bags. In PVC bags, however, up to 55% of diazepam, 23% of isosorbide dinitrate, 51% of nitroglycerin, and 24% of warfarin sodium was lost during the 24-hour study period. Diazepam, isosorbide dinitrate, nitroglycerin, and warfarin sodium in 0.9% sodium chloride injection showed a loss of potency when stored in PVC containers for 24 hours at room temperature, but none of the drugs studied lost potency when stored in glass bottles and Clear-Flex bags.

Analysis of water-soluble vitamins in total parenteral nutrition solution by high pressure liquid chromatography.

A stability-indicating high pressure liquid chromatographic method was developed to determine the stability of water-soluble vitamins in total parenteral nutrition mixtures. Folic acid and thiamine were determined by direct injection and precolumn enrichment, followed by UV detection. Nicotinamide and pyridoxine were determined simultaneously without sample pretreatment by UV detection of nicotinamide and fluorescence detection of pyridoxine. Riboflavin 5'-phosphate was also determined without elaborate sample handling and by fluorescence detection. Ascorbic acid was determined as the sum of ascorbic acid and dehydroascorbic acid. After derivatization to a quinoxaline the latter substance was determined by direct injection and fluorescence detection.

Investigation of protein structure by means of 19F-NMR. A study of hen egg-white lysozyme.

A 19F-labeled derivative of hen egg-white lysozyme, in which the six epsilon-amino groups are trifluoroacetylated (LF6), was prepared by reaction of lysozyme with S-ethyltrifluorothioacetate. The reaction mixture was fractionated by cation-exchange chromatography at pH 7.3. A comparison of the circular dichroic spectra and the activity towards Micrococcus lysodeikticus of both LF6 and native lysozyme reveals that the labeling causes no major conformational changes of the polypeptide backbone. Assignment of the six resonances present in the 19F-NMR spectrum of LF6 was accomplished by using a variety of techniques: specific chemical modifications, the effect of the inhibitor (GlcNAc)3, 19F-shift/pH information and relaxation parameters.